Genome-Wide Transcriptome Architecture in a Mouse Model of Gulf War Illness

Details

• Personal Author:
  Ashbrook DG ; Gao J ; Jones BC ; Lu L ; Miller DB ; O'Callaghan JP ; Starlard-Davenport A ; Williams RW ; Xu F ; Zhao W
• Description:
  Gulf War Illness (GWI) is thought to be a chronic neuroimmune disorder caused by in-theater exposure during the 1990-1991 Gulf War. There is a consensus that the illness is caused by exposure to insecticides and nerve agent toxicants. However, the heterogeneity in both development of disease and clinical outcomes strongly suggests a genetic contribution. Here, we modeled GWI in 30 BXD recombinant inbred mouse strains with a combined treatment of corticosterone (CORT) and diisopropyl fluorophosphate (DFP). We quantified transcriptomes from 409 prefrontal cortex samples. Compared to the untreated and DFP treated controls, the combined treatment significantly activated pathways such as cytokine-cytokine receptor interaction and TNF signaling pathway. Protein-protein interaction analysis defined 6 subnetworks for CORT + DFP, with the key regulators being Cxcl1, Il6, Ccnb1, Tnf, Agt, and Itgam. We also identified 21 differentially expressed genes having significant QTLs related to CORT + DFP, but without evidence for untreated and DFP treated controls, suggesting regions of the genome specifically involved in the response to CORT + DFP. We identified Adamts9 as a potential contributor to response to CORT + DFP and found links to symptoms of GWI. Furthermore, we observed a significant effect of CORT + DFP treatment on the relative proportion of myelinating oligodendrocytes, with a QTL on Chromosome 5. We highlight three candidates, Magi2, Sema3c, and Gnai1, based on their high expression in the brain and oligodendrocyte. In summary, our results show significant genetic effects of the CORT + DFP treatment, which mirrors gene and protein expression changes seen in GWI sufferers, providing insight into the disease and a testbed for future interventions. [Description provided by NIOSH]
• Subjects:
  Air Pollutants, Occupational Animals Environmental Exposure Genetics Hazardous Substances Insecticides Laboratories Nervous System Occupational Health Risk Assessment Risk Factors Safety

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• Keywords:
  Author Keywords: BXD RI Mice Cytokines Exposure Levels Genes Gulf War Illness Health Effects Laboratory Animals Nerve Damage Nerves Neuroinflammation Proteins Risk Factors Toxic Effects Toxic Gases Toxins Transcriptome

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• ISSN:
  0889-1591
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; OSHA Region 4 ; Tennessee ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  209-223
• Volume:
  89
• NIOSHTIC Number:
  nn:20060169
• Citation:
  Brain Behav Immun 2020 Oct; 89:209-223
• Contact Point Address:
  Lu Lu, Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163
• Email:
  llu@uthsc.edu
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4)
• Federal Fiscal Year:
  2021
• Peer Reviewed:
  True
• Source Full Name:
  Brain, Behavior, and Immunity
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:2569aae70c05fb472b639da4843df175b9a861af57c4191734142193633854e2d00b9f2b77f275d474a6be01695b736114f293d23557af7ffdf92830e602c225
• Download URL:
  https://stacks.cdc.gov/view/cdc/224163/cdc_224163_DS1.pdf
• File Type:
  [PDF - 952.08 KB ]